INTRODUCTION
The opioid epidemic is an unprecedented health crisis affecting North America with over 80,800 deaths in the United States in 2021 attributable to opioids.1 2,3 4–7
In the ever-changing landscape of the illicit drug supply, benzodiazepines like etizolam have also become increasingly prevalent contaminants in the illicit opioid supply as over 20% of opioid samples tested in Vancouver in 2021 contained benzodiazepines, compared with 9% in 2020.8 9 7
In response to the public health emergency, the BC government created additional overdose prevention services through the newly established Ministry of Mental Health and Addictions, and the Overdose Emergency Response Centre in 2017.10 11 12
Unfortunately, guidelines for naloxone dosing are often outdated and based on expert opinion and experience before the emergence of illicit ultra-potent opioids in 2015.13–15 16–18 18,19 20–22 23
Insite, the first community-supervised consumption site in North America, is at the front lines of the opioid epidemic in Vancouver, BC, providing an observed community location for safe injection drug use.24–26 27 2 saturation monitors, and IM/SC naloxone. This facility maintains records of opioid overdose events and interventions since its inception in 2003, providing a unique insight into overdose trends in communities with increasing fentanyl prevalence in the illicit drug supply.
Our primary objective was to assess the evolving trends in overdoses, naloxone dosing, and overdose reversal at Insite, with particular attention to trends following the emergence of illicit fentanyl in BC, that is, 2014–2015 versus 2016–2017. Our secondary objective was to assess the association between the dose of naloxone administered and successful reversal of opioid toxicity at Insite.
METHODS
Study design
In this retrospective cohort study, we reviewed Insite records of patients who overdosed on opioids and were attended by Insite clinicians from March 2014 to November 2017.
Independent, trained data abstractors extracted data from Insite charts using standardized forms. Abstractors were trained to apply a priori definitions of naloxone dose, “confirmed reversal,” “probable reversal,” and disposition (location to which a patient was sent following an overdose event, for example, place of usual residence, hospital) when coding the data.
Population
We included all patients documented to have received naloxone for a suspected opioid overdose at Insite (or nearby) either by an Insite clinician or bystander (n=2619). We included patients who were documented to have overdosed immediately outside of the Insite facility, as these patients would receive the same response as patients who overdosed on site (eg, trained responders with access to resuscitative equipment). We excluded patients not documented to have received naloxone.
Definitions
We defined the initial dose as the first dose of naloxone given, and the cumulative dose as the sum of all naloxone doses given by any route.
Patients were defined as having an opioid overdose if a clinician suspected or confirmed opioid consumption, with associated respiratory depression and/or decreased level of consciousness requiring supplemental oxygen, bag-mask ventilation, or naloxone. Each data point represented one overdose event.
We established an a priori definition of “confirmed reversal” that required the following criteria to be met: 30 minutes after the last naloxone dose, patients had a respiratory rate >11 breaths/minute, Glasgow Coma Score >10, and oxygen saturation >91%.
Anticipating that documentation of all parameters in our “confirmed reversal” definition might be incomplete in many patients, we established an a priori definition of “probable reversal” that required the following criteria to be met: after the last naloxone dose, the patient was documented to be alert and oriented, or walking and talking (eg, conversing with staff or other participants, responding appropriately, and independently ambulatory). If there was documentation of decreased level of consciousness, unresponsiveness, obtundation, incoherent speech, inability to ambulate, or death, patients were defined as “not reversed.”
If criteria for “confirmed reversal” or “probable reversal” were not clearly documented, patient status was marked as “unspecified.”
Interventions
Patients suspected of experiencing an opioid overdose were given an initial dose of naloxone, followed by further doses as necessary. Dosing was guided by the BC Centre for Disease Control clinical decision support tool, starting at 0.4 mg (or 0.4–0.8 mg in the case of muscle rigidity) and additional 0.4 mg doses at 2–3-minute intervals until patients’ respiratory rate was above 10 breaths/minute.28,29
Outcome definitions
The primary outcomes of interest were total overdose count, median naloxone dose, and proportions of overdoses successfully reversed each year between 2014 and 2017. The secondary outcomes were reversal status using both “confirmed reversal” and “probable reversal” definitions, and disposition following naloxone administration. Patient information upon leaving Insite was unavailable.
Data analysis
We analyzed the annual trends in total overdoses seen at Insite, naloxone dose, and proportion of successful reversal from 2014 to 2017. We reported naloxone doses administered as medians with interquartile range (IQR). We compared the proportion of successful reversal between 2014–2015 and 2016–2017 using χ2 tests. In addition, we performed a priori subgroup analyses to determine whether naloxone doses differed based on study year, reversal status, and disposition. We stratified naloxone doses by reversal and disposition status, and compared median doses within these categories using nonparametric Kruskal-Wallis H and pairwise tests.
We performed sensitivity analyses assuming (1) a “best case scenario,” that all overdoses marked unspecified were reversed, and (2) a “worst case scenario,” that all overdoses marked unspecified were not reversed. We chose a “best case scenario” that would provide the most optimistic estimate of naloxone effectiveness. Conversely, our “worst case scenario” sensitivity analysis would provide the most cautious estimate of naloxone effectiveness, allowing a measured interpretation of our results. We planned these sensitivity analyses to mitigate the high degree of unspecified outcomes we anticipated, given the strict reversal definitions we applied.
We also assessed interrater reliability by reviewing a random sample of 150 charts. An independent assessor checked the following variables to assess for accuracy in data extraction and coding: inclusion/exclusion criteria, cumulative naloxone dose, time of naloxone administration, “confirmed reversal” status, “probable reversal” status, and disposition. The overall κ score was 0.895, indicating good interrater reliability among coders for the variables assessed.
Statistical analysis was performed with R (R Foundation for Statistical Computing, Vienna, Austria, version 3.6.1, 2019).
RESULTS
We identified 2619 patients who were managed by Insite clinicians for a suspected opioid overdose from March 2014 to November 2017 (Table 1 ). The majority of patients were male (79.3%), and the most common age group was 30–39 years (27.5%). In addition, most patients (75.2%) were found to have overdosed on-site. Twenty-eight percent of patients were suspected to be apneic on initial assessment and 29.9% unresponsive to stimulation. 93.7% of patients were given supplemental oxygen and other resuscitative interventions. No patients died during their Insite visit.
Table 1 -
Characteristics of Patients and Overdose Events Attended by Insite Clinicians
Characteristics
Frequency
Percentage (%)
Total overdose events
2619
100.0
2014
312
11.9
2015
274
10.5
2016
954
36.4
2017
1079
41.2
Patient characteristics
Sex
Male
2078
79.3
Female
449
17.1
Unspecified
92
3.5
Age (yr)
10–19
36
1.4
20–29
514
19.6
30–39
720
27.5
40–49
545
20.8
50–59
450
17.2
60–69
249
9.5
70+
105
4.0
Overdose event characteristics
Location of overdose
At Insite
1969
75.2
Off-site
529
20.2
Unspecified
121
4.6
Suspected respiratory arrest
Yes
743
28.4
No
419
16.0
Unspecified
1457
55.6
Completely unresponsive to stimulation
Yes
784
29.9
No
325
12.4
Unspecified
1510
57.7
Other illicit substances recorded
Yes
316
12.1
No (patient denies)
355
13.6
Unspecified
1948
74.4
Oxygen supplementation provided
Yes
2454
93.7
No
84
3.2
Unspecified
81
3.1
We observed an increase in the numbers of documented opioid overdoses at Insite, and decreased rates of successful reversal in 2016–2017 compared with 2014–2015 (Fig. 1 ). Insite staff responded to 2033 opioid overdoses in 2016–2017 compared with 586 in 2014–2015. Based on the “confirmed reversal” definition, fewer patients were successfully reversed after 2015 (25.8% in 2016, 22.9% in 2017) than during and before 2015 (31.4% in 2014, 28.8% in 2015, χ2 =10.4, P <0.001) (Fig. 1A ). Similarly, we observed decreased proportions of reversal after 2015 using our “probable reversal” definition (47.8% in 2014, 55.1% in 2015, 44.1% in 2016, and 29.7% in 2017, χ2 =73.1, P <0.001) (Fig. 1B ).
Figure 1: Reversal status by visit year based on: (A) “confirmed reversal” criteria. B, “Probable reversal” criteria.
We found that the initial naloxone dose (0.4 mg) remained unchanged throughout the study period (2014–2017) and found no significant difference in initial dose among all subgroups based on reversal status and disposition (probable reversal: Kruskal-Wallis H =2.2, P =0.33; confirmed reversal: Kruskal-Wallis H =4.0, P =0.14; disposition: Kruskal-Wallis H =4.5, P =0.20). Similarly, we found no significant difference in the cumulative naloxone doses between patients treated in 2014–2015 compared with those in 2016–2017 [median: 0.4 mg (IQR: 0.4–0.8 mg) for both, Kruskal-Wallis H =1.7, P =0.21].
In 2014–2015, 130 (73.9%) patients were given 1 dose, 39 (22.2%) were given 2 doses, and 7 (4.0%) were given 3 doses of naloxone among those who were “confirmed” reversed. Similarly, in 2016–2017, 366 (74.2%) patients were given one dose of naloxone, 112 (22.7%) were given 2 doses, and 15 (3.0%) were given 3 doses among those “confirmed” reversed. In contrast, among patients not reversed in 2014–2015, 8 (42.1%) received 1 dose, 9 (47.4%) received 2 doses, and 2 (10.5%) received 3 doses of naloxone. Among those not reversed in 2016–2017, 18 (36.7%) received 1 dose, 24 (49.0%) received 2 doses, and 7 (14.3%) received 3 doses of naloxone.
We determined that cumulative naloxone doses were higher in patients not successfully reversed than those reversed based on both the “confirmed” [unsuccessful: median: 0.8 mg (IQR: 0.4–0.8 mg); successful: median: 0.4 mg (IQR 0.4–0.8 mg), Kruskal-Wallis H =490.0, P <0.001] and “probable” reversal definitions (unsuccessful: median: 0.8 mg (IQR: 0.4–0.8 mg); successful: median: 0.4 mg (IQR: 0.4–0.8 mg), Kruskal-Wallis H =246.4, P =0.021] (Table 2 , Fig. 2A ). We also observed that doses were higher in patients transferred or declined transfer to hospital [median: 0.8 mg (IQR: 0.4–0.8 mg)], compared with patients discharged home [median: 0.4 mg (IQR: 0.4–0.8 mg), Kruskal-Wallis H =288.7, P <0.001] (Table 2 , Fig. 2B ).
Table 2 -
Cumulative Naloxone Dose Stratified by Reversal and Disposition Status Following Insite Visit
N
Median dose (mg)
IQR (mg)
Reversal Status
“Confirmed reversal”
No
68
0.8
0.4–0.8
Yes
670
0.4
0.4–0.8
Unspecified
1881
0.4
0.4–0.8
“Probable reversal”
No
40
0.8
0.4–0.8
Yes
1042
0.4
0.4–0.8
Unspecified
1537
0.4
0.4–0.8
Disposition status
Hospital
566
0.8
0.4–0.8
Refused hospital
585
0.8
0.4–0.8
Home
772
0.4
0.4–0.8
Unspecified
696
0.4
0.4–0.8
Figure 2: Cumulative naloxone dose stratified by (A) reversal status. B, Disposition following Insite visit.
In our sensitivity analyses, if we assumed a “best case scenario” wherein all unspecified cases were reversed, cumulative naloxone doses were higher in patients who were not reversed than those reversed using both confirmed [unsuccessful: median: 0.8 mg (IQR: 0.4–0.8 mg); successful: median: 0.4 mg (IQR: 0.4–0.8 mg), Kruskal-Wallis H =16.5, P <0.001] and probable definitions (unsuccessful: median: 0.8 mg (IQR: 0.8–1.0 mg); successful: median: 0.4 mg (IQR: 0.4–0.8 mg), P =0.007]. On the contrary, if we assumed a “worst case scenario” wherein all unspecified cases were not reversed, cumulative doses administered to those who were and were not reversed were significantly different, though the direction of the difference was not clear [confirmed reversal—unsuccessful: median: 0.4 mg (IQR: 0.4–0.8 mg); successful: median: 0.4 mg (IQR: 0.4–0.8 mg), Kruskal-Wallis H =53.5, P <0.001. Probable reversal—unsuccessful: median: 0.4 mg (IQR: 0.4–0.8 mg); successful: median: 0.4 mg (IQR: 0.4–0.8 mg), Kruskal-Wallis H =5.4, P =0.02].
DISCUSSION
Interpretation of findings
We aimed to understand the trends in overdoses, naloxone dosing, and reversal status over time at Insite, a community-supervised consumption site in Vancouver, BC. Insite provided an unparalleled opportunity to explore longitudinal trends in overdose incidence and management, in a setting and population that is challenging to study. Our data showed that the number of overdoses increased markedly after December 31, 2015, following the emergence of fentanyl in BC’s illicit drug supply. Fewer patients were defined as “successfully reversed” in 2014–2015 than in 2016–2017, while cumulative naloxone doses administered remained unchanged. We also showed that clinicians used higher naloxone doses in patients not successfully reversed than reversed, and in those offered transport to the hospital compared with those discharged home, both likely proxies of opioid overdose severity.
The increased number of overdoses at Insite over time likely reflects increasing overdose severity (ie, apnea and/or complete unresponsiveness) with exposure to illicit fentanyl. BC public health data showed that illicit drug deaths in which fentanyl was detected increased from 29% in 2015 to 67% in 2016.4 30,31
Our finding that higher naloxone doses, both cumulative dose and number of doses given, were administered to patients not successfully reversed reflects that nonreversal is an indicator of more severe overdose. Similarly, the association between higher doses and being offered transfer to the hospital indicates that disposition is another marker of overdose severity. Patients who were not reversed or were offered transport to the hospital likely experienced a more severe overdose, which resulted in higher naloxone doses, and a greater number of doses administered, and reflects confounding by indication. Our finding that greater proportions of patients who were not reversed received multiple doses of naloxone in 2016–2017 than in 2014–2015 suggests that the severity of overdoses increased in the later years of our study when the prevalence of fentanyl increased in the illicit drug supply.
Comparison to previous studies
A recent study showed that fentanyl was increasingly detected by patients using drug testing services at Insite post-2015, which confirms our suspicion that growing fentanyl prevalence underlies the increase in overdose numbers in our study population at Insite.32 33
Strengths and limitations
Our study analyzed overdose and naloxone data in a community population that is challenging to research due to a lack of data and trained providers. Insite, a supervised consumption site, provides an unprecedented opportunity to understand trends in overdose, naloxone dosing, and overdose reversal in a community setting, and provides higher quality longitudinal data (2014–2017) than previously available.
Despite access to this data, our study was limited by inconsistent documentation. Due to incomplete documentation, our abstractors determined that a high proportion of patient reversal statuses were “unspecified” using the “confirmed reversal” definition [n=1881/2619 (71.8%)]. We attempted to minimize this limitation by including a “probable reversal” definition, but a large proportion of overdose outcomes were still marked as “unspecified” due to incomplete documentation [n=1537/2619 (58.7%)]. In our assessment of reversal trends over time, we primarily used the proportion of patients who were marked as “reversed,” though we also did assess the trends of patients marked “not reversed.” Unfortunately, there was no clear trend in this population, likely as a result of stringent criteria (ie, postnaloxone respiratory rate, GCS, and oxygen saturation that did not meet criteria for reversal), which was not available in many participant charts, as well as our hypothesis that Insite clinicians were less likely to have documented completely in patients who were not reversed as they would be busy attending to clinical care. For these reasons, we focused our discussion on reversal trends on patients who were marked “reversed” than those “not reversed” as we believe that this is a more reliable measure.
To mitigate the impact of incomplete documentation, we completed sensitivity analyses. In a “best case” scenario, we continued to find that patients who were not reversed received higher naloxone doses. However, in a “worst case” scenario, patients who were reversed and not reversed received similar naloxone doses. Our differential findings on sensitivity analyses do indicate limitations of our data, and emphasize that our analyses are exploratory rather than definitive. Similarly, the lack of clear documentation made it challenging to ascertain important variables including patient co-morbidities/risk factors, which could influence successful overdose reversal and the dose of naloxone required. Despite data limitations, our analysis provides important observations about opioid overdose reversal in community settings that provide an important basis for future, definitive analyses in more rigorous trials.
Based on our clinical and experiential knowledge of Insite procedures, we expect documentation of naloxone doses to be more accurate than information requiring clinical assessment of patients. Nonetheless, our analyses are reliant on dosing information we abstracted from charts and potential inaccuracies are a limitation. In addition, patients with overdoses who were transported to the hospital may have received additional naloxone and potentially demonstrated further clinical response upon leaving Insite, but this data was unavailable. This may have led to inaccurate assessments of total naloxone doses administered, and misclassification of reversal status if treatment and clinical response progressed.
Finally, our data is current only until 2017, due to delays in data acquisition and the labour-intensive process of data extraction. The constantly changing landscape of the illicit drug supply (eg, fluctuating levels of ultra-potent opioids) make it challenging to establish recommendations for naloxone administration specifically tailored to current realities.34 8
Clinical and research implications
Our data showed that the proportions of overdoses that were successfully reversed at Insite decreased over time after the emergence of illicit fentanyl in BC, suggesting that our usual approach to naloxone dosing in communities with high fentanyl prevalence is no longer optimal. Although our data do not clarify the preferred approach, alternatives may include more frequent titration of naloxone doses and/or a need for responders to anticipate the need for higher cumulative total doses. Higher naloxone doses may lead to opioid withdrawal in patients with opioid dependence, which is not only extremely unpleasant but also dangerous, as it may lead patients to use opioids again to self-treat withdrawal symptoms.11 35
There is an urgent need to clarify best clinical practices for naloxone dosing in patients suspected of a severe, fentanyl overdose in these communities. Although our data did not allow an evaluation of dosing schedules, further research should specifically assess the effectiveness and safety of more frequent redosing of naloxone than current guidelines suggest (every 2–3 minutes).28,29 36
CONCLUSION
Our study showed that opioid overdoses increased dramatically, and fewer patients were successfully reversed, while naloxone doses remained unchanged at Insite after the emergence of illicit fentanyl in 2015. Therefore, our analysis suggests the need for an alternative approach to naloxone dosing, such as more frequent titration and/or higher cumulative totals, in communities with high fentanyl prevalence.
ACKNOWLEDGEMENTS
The authors thank Mina Karimi, Christine Gillespie, and Mina Park, the managers of Insite for their instrumental role in the conception of this study. They also thank Andrew Chang, Emily Lostchuck, Connor McSweeney, Paul Clerc, and Victoria McCann for their roles in data abstraction.
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